The present invention relates to novel phosphino-gold(I) compounds, to a process for preparing same and to the use of such phosphino-gold(I) compounds for the treatment of cancer.
To date, in the prior art there are only a limited number of efficient anti-cancer drugs available to treat the wide spectrum of cancerous diseases. Amongst the few licensed drugs, cisplatin and its carboplatin derivative (platinum based) are considered to be the most powerful and efficient drugs. These drugs are currently being used almost universally in the treatment of testicular, ovarian and several other forms of cancer. Unfortunately, these drugs also induce major side effects like template inactivation of DNA, destroying rapidly dividing normal body cells and causing serious damage to the bone marrow.
It was discovered In the mid 80s that phosphine-supported gold(I) complexes showed significant anti-tumor activities. Since phosphines are not natural products and are generally difficult to prepare, clinical tests thus far of such anti-cancer gold drugs have been limited to some simple and non-designed phosphines that are available commercially. This has led to irregular and uncontrolled test results.
It would be a significant advance in the art if a new class of anti-cancer drugs could be developed which are effective, and induce minimum side effects.
It is accordingly an object of the present invention to overcome, or at least alleviate, one or more of the difficulties or deficiencies related to the prior art.
Accordingly, in a first aspect of the present invention, there is provided a phosphino-gold(I) compound of formula (I): 
wherein R1, R2, R3, R4 and R5, each of which may be the same or different, are selected from the group consisting of hydrogen, optionally substituted alkyl, aryl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, aryloxy, carboxyalkyl, alkoxycarbonyl, hydroxy, alkylthio, alkylsulfinyl and alkylsulfonyl;
Z is hydrogen or a functional group;
Y is hydrogen or a functional group;
W is hydrogen or a functional group; and
X is a halogen or C(F)3 or C(Cl)3;
in an optically active or racemic form; or a salt thereof.
Alkyl groups preferably contain up to 10 carbon atoms, and more preferably 1 to 4 carbon atoms. The term xe2x80x9calkylxe2x80x9d includes both straight- and branched-chain alkyl groups and cycloalkyl groups. References to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chain version only. An analogous convention applies to other generic terms.
The term xe2x80x9carylxe2x80x9d refers to compounds having one or more aromatic rings having 6 to 16 carbon atoms.
Except as provided otherwise, the terms xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d have the same meaning however used, for example when used alone, or as prefix or suffix.
The term xe2x80x9calkenylxe2x80x9d refers to an alkyl as described above with at least one double bond, it being understood that an xe2x80x9calkenylxe2x80x9d will contain at least 2 carbon atoms.
The term xe2x80x9calkynylxe2x80x9d refers to an alkyl as described above with at least one triple bond, it being understood that an xe2x80x9calkynylxe2x80x9d will contain at least 2 carbon atoms.
By the term xe2x80x9coptionally substitutedxe2x80x9d, we mean that each group may carry one or more of the substituents selected from halo, nitro, cyano, hydroxy, amino, (1-4)C alkyl, (1-4)C alkoxy, and (1-4)C alkylamino.
By the term xe2x80x9chalogenxe2x80x9d, we mean bromide, fluoride, iodide or chloride.
A suitable value for each of R1, R2, R3, R4, and R5 when it is (1-4C)alkyl or for a (1-4C)alkyl substituent is, for example, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
A suitable value for each of R1, R2, R1, R4, and R5 when it is (1-4C)alkoxy or for a (1-4C)alkoxy substituent is, for example, methoxy, ethoxy, propoxy, butoxy or isobutoxy.
A suitable value for R1, R2, R3, R4, and R5 when it is (1-4C)alkylamino or for a (1-4C)alkylamino substituent is, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino or isobutylamino.
The functional groups in position Z, Y and W are selected based on their ability to enhance the hydrophilic property, acidity/alkalinity and to reduce toxicity. without adversely affecting the anti-tumor activity and may be selected from hydroalkyl, alkoxy, aryloxy, carboxyalkyl, alkoxycarbonyl, hydroxy, alkylthio, alkylsulfinyl and alkylsufonyl.
It will be understood that a phosphino-gold(I) compound of the present invention may possess one or more asymmetric carbon atoms and it can therefore exist in diastereoisomeric racemic and optically active forms. It will be understood that the invention encompasses any such form, it being a matter of common general knowledge how various diastereoisomeric forms may be separated and how a racemic compound may be separated into its optically-active forms.
It is also to be understood that the compounds of the present invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
It has surprisingly been found that the phosphino-gold(I) complexes according to the present invention exhibit significant anti-tumor activity but with reduced side effects relative to known anti-tumor agents such as cisplatin and its carboplatin derivatives.
The present invention therefore also relates to a use of a compound of formula (I) in an optically active or racemic form, or a pharmaceutically acceptable salt thereof, to produce an antiproliferative effect in an animal; and to treat cancer. The invention also relates to its use in the manufacture of a medicament for use in the production of an antiproliferative effect; and in the treatment of cancer.
The invention also relates to a process for producing antiproliferative effect, and to a process for treating cancer, comprising administering an effective amount of a compound of formula (I) in an optically active or racemic form or a pharmaceutically acceptable salt thereof. An effective amount refers to an amount effective, at dosages and for periods of time necessary to achieve the desired therapeutic result and may vary according to factors such as the disease state, age, sex and weight of the subject being treated.
In a further aspect of the present invention there is provided a pharmaceutical composition which includes an effective amount of a compound according to the invention and a pharmaceutically acceptable carrier or diluent. It will be understood that any salt of a compound of formula (I) selected for use in the composition is a pharmaceutically acceptable salt. This composition may be used to inhibit the growth and in some cases cause complete regression of tumor cells which are sensitive to the active ingredient which is the compound of formula (I).
The invention also provides a method of preparing a compound according to formula (I) in an optically active or racemic form, or a salt thereof, comprising reacting a compound of the formula shown below, wherein R1, R2, R3, R4 and R5, Z, Y, and W are as described above, with a halo gold (I) compound to form a phosphino-gold (I) compound: 
A suitable pharmaceutically-acceptable salt of an anti-tumor agent of the present invention is, for example, an acid-addition salt of an anti-tumor agent of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
In addition a suitable pharmaceutically-acceptable salt of an anti-tumor agent of the present invention which is sufficiently acidic is an alkali metal salt for example a sodium or potassium salt, an alkalin earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.